Glutamate and α-ketoglutarate: key players in glioma metabolism

Maus, Andreas; Peters, Godefridus J.

doi:10.1007/s00726-016-2342-9

Cited by 95 publications

(75 citation statements)

References 82 publications

(89 reference statements)

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“…The data showed that the levels of glutathione (GSH), glutamate (Glu), and alpha-ketoglutarate (aKG) were most significantly increased in MFN1-overexpressed primary mouse mammary epithelial cells as compared with the control cells (Table S1; n = 3, >2.5fold, p < 0.05). Mitochondrial fusion is linked to enhanced TCA cycle activity (Mishra and Chan, 2016), and aKG, a TCA intermediate metabolite, can be converted to synthesize Glu, which further leads to the synthesis of GSH, an antioxidant that plays a pivotal role in scavenging and reducing mitochondrial and intracellular ROS (Harris et al, 2015;Maus and Peters, 2017;Figure S4E). We found that, similar to ectopic expression of MFN1, TGFb1 treatment led to increased GSH, Glu, and aKG levels, which were reversed upon knockdown of MFN1 in MCF12A cells ( Figures S4F-S4H).…”

Section: Resultsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin

Chen

Kim

et al. 2019

Cell Metabolism

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Graphical AbstractHighlights d EMT induces mitochondrial fusion through upregulation of MFN1 d MFN1 is required for PKCz-mediated NUMB phosphorylation for asymmetric cell division d MFN1-PKCz tethers fused mitochondria for segregation into stem cell progeny d Mitochondrial fusion enhances GSH synthesis to promote stem cell self-renewal In BriefWu et al. reveal that EMT, a key process in cancer progression, activates mitochondrial fusion protein, MFN1, which interacts with cell polarity protein complex to direct asymmetric cell division, allowing stem cell progeny to inherit fused mitochondria with enhanced reactive oxygen species scavenging capacity to sustain the stem cell pool.

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Section: Resultsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin

Chen

Kim

et al. 2019

Cell Metabolism

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“…Consistent with the limited availability of AKG in aged mice, under cold stimulus, DNA demethylation in the Prdm16 promoter was hampered in aged mice. Because AKG is absorbable by cells (Maus & Peters, ), we supplemented middle‐aged mice with AKG and found that dietary supplementation of AKG could elevate their circulatory level and the availability of AKG for beige adipogenesis. We found AKG was elevated in BAT and iWAT after cold exposure, which acted as a cofactor facilitating the DNA demethylation of brown adipogenesis genes.…”

Section: Discussionmentioning

confidence: 99%

“…During aging, however, the cellular metabolic flux declines, which is expected to reduce the AKG concentration in nuclei and thus impede DNA demethylation and brown adipogenesis. As a small molecule, extracellular AKG can be actively absorbed and transported into cells (Burckhardt et al, ; Maus & Peters, ). Thus, we hypothesized that dietary supplementation of AKG could elevate its level in the circulation and, thus, the availability of AKG for beige adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice

et al. 2019

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Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process.Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle-aged mice (10-month-old) compared with young mice (2-month-old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high-fat diet (HFD).These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold-induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle-aged mice. Besides, AKG administration up-regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD-induced obesity in middle-aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene. K E Y W O R D S adipose tissue browning, aging, alpha-ketoglutarate, DNA demethylation, glucose tolerance, high-fat diet S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Tian Q, Zhao J, Yang Q, et al. Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Aging Cell.

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“…The mutated enzyme catalyzes NADP+/NAD+-dependent conversion of isocitrate to 2-hydroxyglutarate (2HG), while the wild type converts isocitrate to α-ketoglutarate. As a consequence this metabolite accumulates in the cell and is further able to affect the demethylating process in the genome (Maus and Peters 2017). Thus 2HG is also known to be an “oncometabolite”.…”

Section: Discussionmentioning

confidence: 99%

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

Cichorek

Ronowska

Gensicka-Kowalewska

et al. 2018

J Cancer Res Clin Oncol

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PurposeAs a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes.MethodsThe cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level.ResultsART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion.ConclusionOur data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2776-4) contains supplementary material, which is available to authorized users.

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Glutamate and α-ketoglutarate: key players in glioma metabolism

Cited by 95 publications

References 82 publications

Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin

Epithelial-Mesenchymal Transition Directs Stem Cell Polarity via Regulation of Mitofusin

Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

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